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Chronicmyeloidleukemia Inchildren: Clinical Findings, Management, and Unanswered Questions
Chronicmyeloidleukemia Inchildren: Clinical Findings, Management, and Unanswered Questions
Chronicmyeloidleukemia Inchildren: Clinical Findings, Management, and Unanswered Questions
in Children
Clinical Findings, Management, and Unanswered
Questions
KEYWORDS
Chronic myeloid leukemia Tyrosine kinase inhibitor
Hematopoietic stem cell transplant BCR-ABL1
KEY POINTS
There are few data showing biological differences between adult and pediatric chronic
myelogenous leukemia (CML), but the clinical presentations are distinct and the host
factors are different in adults and growing children, which raises issues specific to the
care of pediatric patients with CML.
Children have longer life expectancies than adults; therefore, the goal of CML treatment in
children should be cure rather than disease suppression.
Because of the possibility of decades-long tyrosine kinase inhibitor (TKI) treatment, which
also occurs during periods of active growth, morbidity related to TKI therapy for CML is
different in children than in adults. Careful monitoring of bone growth and other possible
long-term morbidity is crucial.
The role of hematopoietic stem cell transplant in the first chronic phase should be defined
for pediatric patients with CML.
INTRODUCTION
a
Division of Hematology, Oncology, and Stem Cell Transplantation, Ann & Robert H. Lurie Chil-
drens Hospital of Chicago, 225 East Chicago Avenue, Box #30, Chicago, IL 60611, USA;
b
Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago,
IL, USA; c Centre dInvestigation Clinique 1402, Institut National de la Sante et de la Recherche
Medicale (INSERM), University Hospital of Poitiers, 2 rue de la Miletrie, 86000 Poitiers, France;
d
Department of Pediatrics, University Hospital Carl Gustav Carus, Fetscherstrasse 74,
D-01307 Dresden, Germany
* Corresponding author. Division of Hematology, Oncology, Stem Cell Transplantation, Ann &
Robert H. Lurie Childrens Hospital of Chicago, 225 East Chicago Avenue, Box #30, Chicago, IL
60611.
E-mail address: nhijiya@luriechildrens.org
accounts for 10% to 15% of myeloid leukemia and is more common than acute
promyelocytic leukemia, which accounts for 5% to 10% of cases. At one time,
hematopoietic stem cell transplant (HSCT) was the only curative treatment of CML
in children as well as in adults; however, the treatment landscape has changed dras-
tically over the last 15 years since the introduction of the tyrosine kinase inhibitor (TKI)
imatinib.46 Continuing TKI treatment indefinitely has become standard practice for
adult patients in chronic phase (CP), and the feasibility of discontinuing TKI therapy
in patients in deep molecular remission has been studied.7 However, because of a
lack of data from large clinical studies, standardized treatment and interventions
have not been established in the pediatric CML population. This article discusses
some controversial issues and unanswered questions (Table 1), as well as current
recommendations, in the management of pediatric CML (Boxes 1 and 2, Fig. 1).
Table 1
Unanswered questions and issues specific to pediatric CML
Abbreviations: 2G, second generation; ELN, European Leukemia Net; iBFM, international Berlin-
Frankfurt-Munster study group; NCCN, National Comprehensive Cancer Network.
Chronic Myeloid Leukemia in Children 109
Box 1
Recommended tests to monitor disease status
At diagnosis:
1. Bone marrow (cytogenetics, FISH)
2. Qualitative PCR for BCR-ABL1
3. Consider HLA typing of the patient and siblings
During TKI treatment:
1. Bone marrow every 3 months until complete cytogenetic remission (no Philadelphia
chromosome is identified)
2. RQ-PCR by peripheral blood every 3 months
3. BCR-ABL1 mutation analysis if response is not optimal
There are some differences in the clinical presentation of CML at diagnosis in chil-
dren and adults, which suggests different underlying biology. The median baseline
white blood cell count (WBC) in adult patients with CML ranges from 80 109/L
to 150 109/L,810 but is higher in children with CML; WBC was reported to be
approximately 250 109/L in an international registry of 200 children with CML (me-
dian age, 11.6 years; range, 8 months to 18 years).11 Compared with older adults,
adolescents and young adults (1629 years) also present with higher WBC as well
as other aggressive disease features (larger spleen, higher peripheral blast counts,
and lower hemoglobin levels), although one study showed similar outcomes.12
Another study showed less favorable cytogenetic and molecular response rates
and a trend for shorter event-free survival in a similar age group (1529 years) of
patients with CML compared with older adults, although overall survival rates were
not different.13 The median size of the spleen is 8 cm below the costal margin (range,
025 cm)11 in children, which is not very different from adults.14 However, the age-
based normal size of the spleen in children is smaller than in adults; therefore,
Box 2
Recommended monitoring of morbidities and supportive care
Height, weight and Tanner staging on every visit. If there are abnormal patterns, consult
endocrinology and consider bone age and DEXA scan.
Thyroid function after 4 to 6 weeks of TKI and repeat thereafter periodically.
Echocardiogram and ECG annually.
Inactivated vaccines may be given anytime during TKI treatment, although efficacy is not
confirmed.
Live vaccines are not recommended during TKI therapy. May be given after discontinuing TKI
for several weeks when the patient is in deep molecular response.
imatinib, and prognostic scores were inconsistent in children and did not predict poor
response at 3 months.
More recently, cytogenetic and molecular responses to TKI therapy have been
used as prognostic markers. NCCN19 and ELN20 guidelines use TKI responses at
3, 6, and 12 months to define treatment failure or to recommend change of treat-
ment. The prognostic value of early TKI response and kinetics of BCR-ABL1 have
been also described25,26 but they need to be evaluated in pediatric patients with
CML.
Table 2
Published results of HSCT for children with CML in first CP
Only studies with data for greater than 100 patients are listed.
Abbreviations: CP1, first chronic phase; MMD, mismatched donor; MRD, matched-related donor;
MSD, matched-sibling donor; MUD, matched-unrelated donor; VUD, volunteer-unrelated donor.
Chronic Myeloid Leukemia in Children 113
Role of Newer Tyrosine Kinase Inhibitors for Pediatric Chronic Myelogenous Leukemia
Imatinib has been successfully studied in pediatric phase 1, 2, and 4 studies,5,6,72 and
was approved as first-line treatment of children with CML in 2003 by the US Food
and Drug Administration (FDA) and the European Medical Agency (EMA). The
second-generation (2G) TKIs dasatinib73,74 and nilotinib75 have been shown to
produce a more rapid and deeper response in adults, and are now included as first-
line treatments for adults with CML in CP in the most recent guidelines from ELN20
and NCCN.19 Dasatinib76,77 and nilotinib (clinicaltrials.gov, NCT01077544) have
been tested in phase 1 trials in the pediatric patient population and there are ongoing
phase 2 trials (NCT00777036). A phase 2 study of nilotinib (NCT01844765) is currently
being conducted in the Childrens Oncology Group and Innovative Therapies for
Children with Cancer. Another 2G TKI (bosutinib),78 a third-generation TKI (ponatinib)
that has been shown to be active against T315I mutation,79 and a protein translation
inhibitor (omacetaxine mepesuccinate)80 are all approved for resistant or intolerant
CML in adults, but have not yet been investigated in children.
domain (TKD) mutation analysis should be performed. Depending on the TKD muta-
tion and the sensitivity,20 the patient should receive an alternative TKI,19,83 if available
to children. At the same time, an HSCT donor search is recommended. HSCT should
also be considered in certain circumstances such as noncompliance, serious side ef-
fects with TKIs, availability of a donor, and patient choice following appropriate coun-
seling on the balance of risk and benefit of cure.
There is no standard for monitoring of morbidities in pediatric CML and more data
are needed. The currently suggested monitoring schedule is shown in Box 2. Lack of
knowledge about immune dysfunction with TKI84 is hindering routine vaccination for
children with CML. A study showed that adult patients treated with TKI had an
impaired immunoglobulin M (IgM) humoral response to pneumococcal vaccine
compared with healthy controls and reduction of IgM-memory B cells through off-
target inhibition of kinases.84 It is safe to give inactivated vaccines to children on
TKI therapy, although there may be an insufficient response as in any immunocom-
promised patient. However, one report indicated a higher seroconversion rate to
H1N1 influenza vaccine in adult patients with CML compared with patients with B-
cell malignancies or HSCT recipients.85 The study evaluated 32 adult patients with
CML receiving imatinib (n 5 23) or dasatinib (n 5 9). Protective antibody titers
were observed in 85% (P 5 .086) and 95% (P 5 .5) of the patients with CML after
the first and second doses, respectively, compared with controls (100% after the first
dose).85 Giving live vaccines during TKI treatment is not recommended in general,
although one study suggests that varicella vaccine can be given to some immuno-
compromised children.86 As an alternative, when a deep molecular response is
achieved after a few years of TKI treatment, the TKI treatment may be interrupted
for several weeks to provide a window for administering live vaccines. In the United
States, all live vaccines are completed by the age of 4 to 6 years (http://www.cdc.
gov/vaccines/). Because CML is rarely seen in children before this age, few patients
face this issue.
SUMMARY
There are few data showing differences in the biology of CML in children and adults,
but host factors in growing children are distinct from those of adults, which raises
issues specific to the care of pediatric patients with CML. The goal of treatment in
pediatric CML should be cure rather than disease suppression, which can be the
goal in many adult patients. Morbidity associated with TKI therapy is different in
growing children than in adults. The possible indication of HSCT in first CP should
be defined for the pediatric patient population. Large studies are urgently needed
to improve understanding of the unique biology and long-term morbidities in children
with CML, thus preparing for the creation of pediatric-specific guidelines for treat-
ment and follow-up.
ACKNOWLEDGMENTS
The authors thank Stacey Tobin, PhD, and Michael Miller, MD, for assistance in
preparation of this article, and Briana Patterson, MD, for valuable discussion.
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